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Analysis of onset mechanism in refractory glomerulonephritis with DNA microanray

DNA显微分析难治性肾小球肾炎发病机制

基本信息

批准号：
13671104
负责人：
UENO Mitsuhiro
金额：
$ 2.18万
依托单位：
Niigata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

Both IgA nephropathy and crescentic glomerulonephritis are typical of refractory glomerulonephritis. The precise onset mechanisms of both glomerulonephtitis are unknown. However genetical factors may be associated with the onset of IgA nephropathy because of familial clustering. We attempted to investigate the possible role of various gene polymorphisms in IgA nephropathy and studied any possible associations between gene variation and the clinical manifestations, especially renal prognosis in about 250 patients. As a result, we demonstrated that single nucleotide polymorphisms of polymeric immunoglobulin receptor, uteroglobin, angiotensin converting enzyme angiotensinogen aldosterone synthase, SA, α addducin and peroxisome proliferator-activated receptor γ were related to renal prognosis of IgA nephropathy.Rat anti-glomerular basement membrane(GBM) nephritis is a model of crescentic glomerulonepnntis induced by the administration of anti-GBM antiserum. To elucidate the mechanism of gl … More omerular injury, we analyzed the gene expression patterns in the kidneys of anti-GBM nephritis rats using DNA arrays, and found that macropgage metalloelastase/matrix metalloproteinase(MMP)-12 was lone of the highly expressed genes in the kidneys on days 3 and 7 after the injection of anti-GBM antiserum. Enhancement of MMP-12 mRNA expression was confirmed by Northern blot analysis, and in situ hybridization revealed that MMP-12 mRNA was expressed in ED-1-positive macrophages and multinuclear giant cells in the glomeruli with crescent. Moreover, these cells were positive with anti-rat rMMP-12 Ab on the section of the kidneys of anti-GBM nephritis rats on day 7. To clarify the role of MMP-12, we conducted a neutralization experiment using anti-rat rMMP-12 Ab. Consequently, crescent formation and macrophage infiltration in the glomeruli were significantly rethiced in the rats treated with anti-rat rMMP-12 Ab, and the amount of urine protein was also decreased. These results disclosed that MMP-12 played an important role in glomerular injury in a crescentic glomerulonephritis model. Less

伊加肾病和新月体肾炎都是典型的难治性肾小球肾炎。这两种肾小球肾炎的确切发病机制尚不清楚。然而，由于家族聚集性，遗传因素可能与伊加肾病的发病有关。我们试图调查各种基因多态性在伊加肾病中的可能作用，并研究基因变异与临床表现，特别是肾脏预后之间的任何可能的关联。结果表明，多聚免疫球蛋白受体、子宫珠蛋白、血管紧张素转换酶、血管紧张素原醛固酮合成酶、SA、α adducin和过氧化物酶体增殖物激活受体γ的单核苷酸多态性与伊加肾病的预后有关。阐明gl的作用机制 ...更多信息本研究应用DNA芯片技术分析了抗GBM肾炎大鼠肾脏基因表达谱，发现巨噬细胞金属弹性蛋白酶/基质金属蛋白酶（MMP）-12是注射抗GBM抗血清后第3天和第7天肾脏中唯一高表达的基因。北方印迹分析证实MMP-12 mRNA表达增强，原位杂交显示MMP-12 mRNA在新月体肾小球内表达于艾德-1阳性的巨噬细胞和多核巨细胞。此外，这些细胞在第7天的抗GBM肾炎大鼠的肾切片上与抗大鼠rMMP-12 Ab呈阳性。为了阐明MMP-12的作用，我们使用抗大鼠rMMP-12 Ab进行了中和实验。因此，在用抗大鼠rMMP-12 Ab治疗的大鼠中，肾小球中新月体形成和巨噬细胞浸润显著增加，并且尿蛋白量也减少。这些结果表明，MMP-12在新月体肾小球肾炎模型中的肾小球损伤中发挥重要作用。少